The central hypothesis of this proposal is that Leishmania spp. are able to manipulate both the innate and the adaptive immune responses of the host to their advantage. The first aim of the proposal focuses on the ability of Leishmania to manipulate the innate immune response, and the second aim focuses on the ability of the parasite to manipulate the adaptive immune response. The proposal is built on two separate and surprising observations that were made in the lab. The first aim of the proposal is built on the observation that infection of macrophages and DC with Leishmania promastigotes fails to induce cytokine production or APC maturation. Thus we hypothesized that Leishmania fail to engage the innate immune responses of the host. The main question we will ask in Aim 1 is whether this failure to activate innate immunity is a critical component to parasite virulence. To ask this question, we have developed transgenic Leishmania that do engage Toll-Like Receptors (TLRs) on macrophages and DC. We plan to study the biology of these organisms and determine whether they are presented to T cells differently, whether they cause lesions that are different from wild-type organisms, and whether they induce qualitatively and quantitatively different adaptive immune responses. The second aim is based on the observation that mice lacking the heavy chain of IgG (JH mice) are resistant to L. major infection, despite being on the susceptible BALB/c background. The infusion of immune serum into these mice actually increases lesion progression and parasite replication. We plan to determine how IgG can work to the detriment of the host infected with an intracellular parasite. We hypothesize that IgG leads to IL-10 production by APCs, and we will determine the extent to which APCderived IL-10 influences adaptive immune responses to this organism. We will determine which aspects of the adaptive immune response are altered by the presence of IgG immune complexes. These studies not only pertain directly to Leishmania immunity, but they may also provide basic general information about theimmune resonse to intracellular pathogens, and about the role of APCs in modulating adaptive immune responses.